Treatment for diabetes in patients inappropriate for metformin therapy

ABSTRACT

The present invention relates to the finding that certain DPP-4 inhibitors are particularly suitable for treating and/or preventing metabolic diseases, particularly diabetes, in patients for whom metformin therapy is inappropriate due to intolerability or contraindication against metformin.

The present invention relates to certain DPP-4 inhibitors for treatingand/or preventing metabolic diseases, particularly diabetes (especiallytype 2 diabetes mellitus) and conditions related thereto, in patientsfor whom normal metformin therapy is not appropriate (due tointolerability or contraindication against metformin), as well as to theuse of these DPP-4 inhibitors in said treatment and/or prevention.Pharmaceutical compositions and combinations for treating and/orpreventing metabolic diseases (particularly diabetes) in these patientscomprising a DPP-4 inhibitor as defined herein optionally together withone or more other active substances are also contemplated.

Type 2 diabetes mellitus is a common disease of increasing prevalenceworldwide and may be associated with macrovascular complications such ascardiovascular disease, and/or microvascular complications such asblindness, neuropathy and/or renal impairment or failure.

There are various reasons why renal impairment can occur in people withdiabetes. One of the typical long-term complications of diabetes isdiabetic nephropathy, which can progress to renal failure in some cases.

Although intensive treatment of hyperglycemia can reduce the incidenceof chronic damages, many patients with type 2 diabetes remaininadequately treated, partly because of limitations in long termefficacy, tolerability and dosing inconvenience of existingantihyperglycemic therapies.

Diet therapy and exercise therapy are essential in the treatment ofdiabetes mellitus. When these therapies do not sufficiently control theconditions of patients (especially their blood sugar level), an oral ornon-oral antidiabetic agent is additionally used for the treatment ofdiabetes. Conventional antidiabetic or antihyperglycemic agents include,without being limited to, metformin, sulphonylureas, thiazolidinediones,glinides, alpha-glucosidase blockers, GLP-1 and GLP-1 analogues, as wellas insulin and insulin analogues. However, the use of these conventionalantidiabetic or antihyperglycemic agents can be associated with variousadverse effects. For example, metformin can be associated with lacticacidosis or gastrointestinal side effects; sulfonylureas, glinides andinsulin or insulin analogues can be associated with hypoglycemia orweight gain; thiazolidinediones can be associated with edema, bonefracture, weight gain or heart failure/cardiac effects; andalpha-glucosidase blockers and GLP-1 or GLP-1 analogues can beassociated with gastrointestinal adverse effects (e.g. dyspepsia,flatulence or diarrhea, or nausea or vomiting).

Metformin is an antihyperglycemic agent which improves glucose tolerancein patients with type 2 diabetes mellitus. Metformin can be used aloneor combined with other antihyperglycemic medications to improve glycemiccontrol in metformin responsive type 2 diabetes patients. Metformin canalso be of value in the treatment of obese or overweight diabeticpatients or in patients with polycystic ovary syndrom. However,treatment with metformin can be associated with adverse symptoms, suchas e.g. gastrointestinal symptoms or, occasionally, as a severe adverseeffect, lactic acidosis (which can be fatal), for which one putativerisk factor is decreased renal function. Further, since metformin islargely eliminated unchanged by the kidneys via glomerular filtrationand tubular secretion, it is contraindicated in patients with renaldisease or renal impairment. Thus, conventional metformin therapy can beinappropriate for certain patients, e.g. due to intolerability orcontraindication against metformin. The number of patients who are thusineligible for metformin can be quite large and may include aconsiderable percentage of those who might otherwise benefit from themedication. Therefore, it remains a need in the art to provideefficacious, safe and tolerable antidiabetic therapies for thesediabetic patients ineligible for metformin therapy.

In the monitoring of the treatment of diabetes mellitus the HbA1c value,the product of a non-enzymatic glycation of the haemoglobin B chain, isof exceptional importance. As its formation depends essentially on theblood sugar level and the life time of the erythrocytes the HbA1c in thesense of a “blood sugar memory” reflects the average blood sugar levelof the preceding 4-12 weeks. Diabetic patients whose HbA1c level hasbeen well controlled over a long time by more intensive diabetestreatment (i.e. <6.5% of the total haemoglobin in the sample) aresignificantly better protected from diabetic microangiopathy. Theavailable treatments for diabetes can give the diabetic an averageimprovement in their HbA1c level of the order of 1.0-1.5%. Thisreduction in the HbA1C level is not sufficient in all diabetics to bringthem into the desired target range of <7.0%, preferably <6.5% and morepreferably <6% HbA1c.

Within glycemic control, in addition to improvement of the HbA1c level,other recommended therapeutic goals for type 2 diabetes mellituspatients are improvement of fasting plasma glucose (FPG) and ofpostprandial plasma glucose (PPG) levels to normal or as near normal aspossible. Recommended desired target ranges of preprandial (fasting)plasma glucose are 90-130 mg/dL or <110 mg/dL, and of two-hourpostprandial plasma glucose are <180 mg/dL or <140 mg/dL.

Within the meaning of this invention, inadequate or insufficientglycemic control means in particular a condition wherein patients showHbA1c values above 6.5%, in particular above 7.0%, even more preferablyabove 7.5%, especially above 8%. An embodiment of patients withinadequate or insufficient glycemic control include, without beinglimited to, patients having a HbA1c value from 7.5 to 10% (or, inanother embodiment, from 7.5 to 11%). A special sub-embodiment ofinadequately controlled patients refers to patients with poor glycemiccontrol including, without being limited, patients having a HbA1c value9%.

Patients ineligible for metformin therapy within the meaning of thepresent invention include

-   -   patients for whom metformin therapy is contraindicated, e.g.        patients having one or more contraindications against metformin        therapy according to label, such as for example patients with at        least one contraindication selected from:        -   renal disease, renal impairment or renal dysfunction (e.g.,            as specified by product information of locally approved            metformin),        -   dehydration,        -   unstable or acute congestive heart failure,        -   acute or chronic metabolic acidosis, and        -   hereditary galactose intolerance;            and    -   patients who suffer from one or more intolerable side effects        attributed to metformin, particularly gastrointestinal side        effects associated with metformin, such as for example patients        suffering from at least one gastrointestinal side effect        selected from:        -   nausea,        -   vomiting,        -   diarrhoea,        -   intestinal gas, and        -   severe abdominal discomfort.

Further, due to increased susceptibility for adverse effects, treatmentof elderly patients (e.g. ≥60-70 years) should be often accompanied bycareful monitoring of renal function. Metformin is usually notrecommended in elderly individuals, particularly ≥80 years, unlessmeasurement of creatinine clearance demonstrates that renal function isnot reduced. Thus, patients ineligible for metformin therapy may alsoinclude, without being limited to, elderly patients, e.g. ≥60-65 yearsor particularly ≥80 years.

A special embodiment of patients ineligible for metformin therapy withinthe meaning of this invention refers to patients having renal disease,renal dysfunction, or insufficiency or impairment of renal function(including mild, moderate and severe renal impairment), e.g. assuggested by elevated serum creatinine levels (e.g. serum creatininelevels above the upper limit of normal for their age, e.g. ≥130-150μmol/l, or ≥1.5 mg/dl (≥136 μmol/l) in men and ≥1.4 mg/dl (≥124 μmol/l)in women) or abnormal creatinine clearance (e.g. glomerular filtrationrate (GFR) ≤30-60 ml/min, e.g. moderate or severe renal impairmentincluding ESRD).

In this context, for more detailed example, mild renal impairment may bee.g. suggested by a creatinine clearance of 50-80 ml/min (approximatelycorresponding to serum creatine levels of ≤1.7 mg/dL in men and ≤1.5mg/dL in women); moderate renal impairment may be e.g. suggested by acreatinine clearance of 30-50 ml/min (approximately corresponding toserum creatinine levels of >1.7 to ≤3.0 mg/dL in men and >1.5 to ≤2.5mg/dL in women); and severe renal impairment may be e.g. suggested by acreatinine clearance of <30 ml/min (approximately corresponding to serumcreatinine levels of >3.0 mg/dL in men and >2.5 mg/dL in women).Patients with end-stage renal disease require dialysis (e.g.hemodialysis or peritoneal dialysis).

For other more detailed example, patients with renal disease, renaldysfunction or renal impairment include patients with chronic renalinsufficiency or impairment, which can be stratified according toglomerular filtration rate (GFR, ml/min/1.73 m²) into 5 disease stages:stage 1 characterized by normal GFR 90 plus either persistentalbuminuria or known structural or hereditary renal disease; stage 2characterized by mild reduction of GFR (GFR 60-89) describing mild renalimpairment; stage 3 characterized by moderate reduction of GFR (GFR30-59) describing moderate renal impairment; stage 4 characterized bysevere reduction of GFR (GFR 15-30) describing severe renal impairment;and terminal stage 5 characterized by requiring dialysis or GFR <15describing established kidney failure (end-stage renal disease, ESRD).

Some otherwise intolerable (gastrointestinal) side effects (like nausea,vomiting, gas, diarrhoea) attributed to metformin may be related to thedose of the medication and thus may be minimized if the dose ofmetformin is reduced. Within the patients of the present invention, inaddition to those patients who should not or can not use metformin,there is a number of patients for whom metformin can be used only in areduced dose, thus the dosage of metformin must be highly individuallyadjusted on the basis of effectiveness, safety and tolerance (e.g. viadose titration), often as a compromise between effectiveness andsafety/tolerability. Therefore, it remains also a need in the art toprovide better (e.g. more efficacious) antidiabetic therapies for thesediabetic patients who need reduced dose metformin therapy due to reducedtolerability, intolerability or contraindication against metformin.

Metformin is usually given in doses varying from about 500 mg to 2000 mgup to 2500 mg per day using various dosing regimens from about 100 mg to500 mg or 200 mg to 850 mg (1-3 times a day), or about 300 mg to 1000 mgonce or twice a day, or delayed-release metformin in doses of about 100mg to 1000 mg or preferably 500 mg to 1000 mg once or twice a day orabout 500 mg to 2000 mg once a day. Particular dosage strengths may be250, 500, 625, 750, 850 and 1000 mg of metformin hydrochloride.

The enzyme DPP-4 (dipeptidyl peptidase IV) also known as CD26 is aserine protease known to lead to the cleavage of a dipeptide from theN-terminal end of a number of proteins having at their N-terminal end aprolin or alanin residue. Due to this property DPP-4 inhibitorsinterfere with the plasma level of bioactive peptides including thepeptide GLP-1 and are considered to be promising drugs for the treatmentof diabetes mellitus.

For example, DPP-4 inhibitors and their uses, particularly their uses inmetabolic (especially diabetic) diseases, are disclosed in WO2002/068420, WO 2004/018467, WO 2004/018468, WO 2004/018469, WO2004/041820, WO 2004/046148, WO 2005/051950, WO 2005/082906, WO2005/063750, WO 2005/085246, WO 2006/027204, WO 2006/029769 orWO2007/014886; or in WO 2004/050658, WO 2004/111051, WO 2005/058901 orWO 2005/097798; or in WO 2006/068163, WO 2007/071738 or WO 2008/017670;or in WO 2007/128721 or WO 2007/128761.

As further DPP-4 inhibitors the following compounds can be mentioned:

-   -   Sitagliptin (MK-0431) having the structural formula A below is        (3R)-3-amino-1-[3-(trifluoromethyl)-5,6,7,8-tetrahydro-5H-[1,2,4]triazolo[4,3-a]pyrazin-7-yl]-4-(2,4,5-trifluorophenyl)butan-1-one,        also named        (2R)-4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine,

In one embodiment, sitagliptin is in the form of its dihydrogenphosphatesalt, i.e. sitagliptin phosphate. In a further embodiment, sitagliptinphosphate is in the form of a crystalline anhydrate or monohydrate. Aclass of this embodiment refers to sitagliptin phosphate monohydrate.Sitagliptin free base and pharmaceutically acceptable salts thereof aredisclosed in U.S. Pat. No. 6,699,871 and in Example 7 of WO 03/004498.Crystalline sitagliptin phosphate monohydrate is disclosed in WO2005/003135 and in WO 2007/050485.

For details, e.g. on a process to manufacture, to formulate or to usethis compound or a salt thereof, reference is thus made to thesedocuments.

A tablet formulation for sitagliptin is commercially available under thetrade name Januvia®. A tablet formulation for sitagliptin/metformincombination is commercially available under the trade name Janumet®.

-   -   Vildagliptin (LAF-237) having the structural formula B below is        (2S)-{[(3-hydroxyadamantan-1-yl)amino]acetyl}pyrrolidine-2-carbonitrile,        also named        (S)-1-[(3-hydroxy-1-adamantyl)amino]acetyl-2-cyano-pyrrolidine,

Vildagliptin is specifically disclosed in U.S. Pat. No. 6,166,063 and inExample 1 of WO 00/34241. Specific salts of vildagliptin are disclosedin WO 2007/019255. A crystalline form of vildagliptin as well as avildagliptin tablet formulation are disclosed in WO 2006/078593.

Vildagliptin can be formulated as described in WO 00/34241 or in WO2005/067976. A modified release vildagliptin formulation is described inWO 2006/135723.

For details, e.g. on a process to manufacture, to formulate or to usethis compound or a salt thereof, reference is thus made to thesedocuments.

A tablet formulation for vildagliptin is commercially available underthe trade name Galvus®. A tablet formulation for vildagliptin/metformincombination is commercially available under the trade name Eucreas®.

-   -   Saxagliptin (BMS-477118) having the structural formula C below        is        (1S,3S,5S)-2-{(2S)-2-amino-2-(3-hydroxyadamantan-1-yl)acetyl}-2-azabicyclo[3.1.0]hexane-3-carbonitrile,        also named        (S)-3-hydroxyadamantylglycine-L-cis-4,5-methanoprolinenitrile,

Saxagliptin is specifically disclosed in U.S. Pat. No. 6,395,767 and inExample 60 of WO 01/68603.

In one embodiment, saxagliptin is in the form of its HCl salt or itsmono-benzoate salt as disclosed in WO 2004/052850. In a furtherembodiment, saxagliptin is in the form of the free base. In a yetfurther embodiment, saxagliptin is in the form of the monohydrate of thefree base as disclosed in WO 2004/052850. Crystalline forms of the HClsalt and the free base of saxagliptin are disclosed in WO 2008/131149. Aprocess for preparing saxagliptin is also disclosed in WO 2005/106011and WO 2005/115982. Saxagliptin can be formulated in a tablet asdescribed in WO 2005/117841.

For details, e.g. on a process to manufacture, to formulate or to usethis compound or a salt thereof, reference is thus made to thesedocuments.

-   -   Alogliptin (SYR-322) having the structural formula E below is        2-({6-[(3R)-3-aminopiperidin-1-yl]-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl}methyl)benzonitrile

Alogliptin is specifically disclosed in US 2005/261271, EP 1586571 andin WO 2005/095381. In one embodiment, alogliptin is in the form of itsbenzoate salt, its hydrochloride salt or its tosylate salt each asdisclosed in WO 2007/035629. A class of this embodiment refers toalogliptin benzoate. Polymorphs of alogliptin benzoate are disclosed inWO 2007/035372. A process for preparing alogliptin is disclosed in WO2007/112368 and, specifically, in WO 2007/035629. Alogliptin (namely itsbenzoate salt) can be formulated in a tablet and administered asdescribed in WO 2007/033266. Formulations of Aloglipitin with metforminor pioglitazone are described in WO 2008/093882 or WO 2009/011451,respectively.

For details, e.g. on a process to manufacture, to formulate or to usethis compound or a salt thereof, reference is thus made to thesedocuments.

-   -   (2S)-1-{[2-(5-Methyl-2-phenyl-oxazol-4-yl)-ethylamino]-acetyl}-pyrrolidine-2-carbonitrile        or a pharmaceutically acceptable salt thereof, preferably the        mesylate, or

(2S)-1-{[1,1,-Dimethyl-3-(4-pyridin-3-yl-imidazol-1-yl)-propylamino]-acetyl}-pyrrolidine-2-carbonitrileor a pharmaceutically acceptable salt thereof:

These compounds and methods for their preparation are disclosed in WO03/037327.

The mesylate salt of the former compound as well as crystallinepolymorphs thereof are disclosed in WO 2006/100181. The fumarate salt ofthe latter compound as well as crystalline polymorphs thereof aredisclosed in WO 2007/071576. These compounds can be formulated in apharmaceutical composition as described in WO 2007/017423.

For details, e.g. on a process to manufacture, to formulate or to usethese compounds or salts thereof, reference is thus made to thesedocuments.

-   -   (S)-1-((2S,3S,11bS)-2-Amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-4-fluoromethyl-pyrrolidin-2-one        or a pharmaceutically acceptable salt thereof:

This compound and methods for its preparation are disclosed in WO2005/000848. A process for preparing this compound (specifically itsdihydrochloride salt) is also disclosed in WO 2008/031749, WO2008/031750 and WO 2008/055814. This compound can be formulated in apharmaceutical composition as described in WO 2007/017423.

For details, e.g. on a process to manufacture, to formulate or to usethis compound or a salt thereof, reference is thus made to thesedocuments.

-   -   (3,3-Difluoropyrrolidin-1-yl)-((2S,4S)-4-(4-(pyrimidin-2-yl)piperazin-1-yl)pyrrolidin-2-yl)methanone        (also named gosogliptin) or a pharmaceutically acceptable salt        thereof:

This compound and methods for its preparation are disclosed in WO2005/116014 and U.S. Pat. No. 7,291,618.

For details, e.g. on a process to manufacture, to formulate or to usethis compound or a salt thereof, reference is thus made to thesedocuments.

-   -   (1((3S,4S)-4-amino-1-(4-(3,3-difluoropyrrolidin-1-yl)-1,3,5-triazin-2-yl)pyrrolidin-3-yl)-5,5-difluoropiperidin-2-one        or a pharmaceutically acceptable salt thereof:

This compound and methods for its preparation are disclosed in WO2007/148185 and US 20070299076. For details, e.g. on a process tomanufacture, to formulate or to use this compound or a salt thereof,reference is thus made to these documents.

-   -   (2S,4S)-1-{2-[(3S,1R)-3-(1H-1,2,4-Triazol-1-ylmethyl)cyclopentylamino]-acetyl}-4-fluoropyrrolidine-2-carbonitrile        (also named melogliptin) or a pharmaceutically acceptable salt        thereof:

This compound and methods for its preparation are disclosed in WO2006/040625 and WO 2008/001195. Specifically claimed salts include themethanesulfonate and p-toluenesulfonate. For details, e.g. on a processto manufacture, to formulate or to use this compound or a salt thereof,reference is thus made to these documents.

-   -   (R)-2-[6-(3-Amino-piperidin-1-yl)-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl]-4-fluoro-benzonitrile        or a pharmaceutically acceptable salt thereof:

This compound and methods for its preparation and use are disclosed inWO 2005/095381, US 2007060530, WO 2007/033350, WO 2007/035629, WO2007/074884, WO 2007/112368, WO 2008/114807, WO 2008/114800 and WO2008/033851. Specifically claimed salts include the succinate (WO2008/067465), benzoate, benzenesulfonate, p-toluenesulfonate,(R)-mandelate and hydrochloride. For details, e.g. on a process tomanufacture, to formulate or to use this compound or a salt thereof,reference is thus made to these documents.

-   -   5-{(S)-2-[2-((S)-2-Cyano-pyrrolidin-1-yl)-2-oxo-ethylamino]-propyl}-5-(1H-tetrazol-5-yl)-10,11-dihydro-5H-dibenzo[a,d]cycloheptene-2,8-dicarboxylic        acid bis-dimethylamide or a pharmaceutically acceptable salt        thereof:

This compound and methods for its preparation are disclosed in WO2006/116157 and US 2006/270701. For details, e.g. on a process tomanufacture, to formulate or to use this compound or a salt thereof,reference is thus made to these documents.

-   -   3-{(2S,4S)-4-[4-(3-Methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl]pyrrolidin-2-ylcarbonyl}thiazolidine        (also named teneligliptin) or a pharmaceutically acceptable salt        thereof:

This compound and methods for its preparation are disclosed in WO02/14271. Specific salts are disclosed in WO 2006/088129 and WO2006/118127 (including hydrochloride, hydrobromide, inter alia).Combination therapy using this compound is described in WO 2006/129785.For details, e.g. on a process to manufacture, to formulate or to usethis compound or a salt thereof, reference is thus made to thesedocuments.

-   -   [(2R)-1-{[(3R)-pyrrolidin-3-ylamino]acetyl}pyrrolidin-2-yl]boronic        acid (also named dutogliptin) or a pharmaceutically acceptable        salt thereof:

This compound and methods for its preparation are disclosed in WO2005/047297, WO 2008/109681 and WO 2009/009751. Specific salts aredisclosed in WO 2008/027273 (including citrate, tartrate). A formulationof this compound is described in WO 2008/144730.

For details, e.g. on a process to manufacture, to formulate or to usethis compound or a salt thereof, reference is thus made to thesedocuments.

-   -   (2S,4S)-1-[2-[(4-ethoxycarbonylbicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile        or a pharmaceutically acceptable salt thereof:

This compound and methods for its preparation are disclosed in WO2005/075421, US 2008/146818 and WO 2008/114857. For details, e.g. on aprocess to manufacture, to formulate or to use this compound or a saltthereof, reference is thus made to these documents.

-   -   2-({6-[(3R)-3-amino-3-methylpiperidin-1-yl]-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydro-5H-pyrrolo[3,2-d]pyrimidin-5-yl}methyl)-4-fluorobenzonitrile        or a pharmaceutically acceptable salt thereof, or        6-[(3R)-3-amino-piperidin-1-yl]-5-(2-chloro-5-fluoro-benzyl)-1,3-dimethyl-1,5-dihydro-pyrrolo[3,2-d]pyrimidine-2,4-dione        or a pharmaceutically acceptable salt thereof:

These compounds and methods for their preparation are disclosed in WO2009/084497 and WO 2006/068163, respectively. For details, e.g. on aprocess to manufacture, to formulate or to use these compounds or saltsthereof, reference is thus made to these documents.

For avoidance of any doubt, the disclosure of each of the foregoingdocuments cited above is specifically incorporated herein by referencein its entirety.

Within the scope of the present invention it has now surprisingly beenfound that DPP-4 inhibitors as defined herein have surprising andparticularly advantageous properties, which make them particularlysuitable for treating and/or preventing (including preventing or slowingthe progression) of metabolic diseases, particularly diabetes(especially type 2 diabetes mellitus) and conditions related thereto(e.g. diabetic complications), particularly in patients for whommetformin therapy is inappropriate due to intolerability orcontraindication against metformin, such as patients ineligible formetformin therapy or patients in need of metformin dose reduction due tointolerability or contraindication against metformin.

Thus, the present invention provides a DPP-4 inhibitor as defined hereinfor use in the treatment and/or prevention of metabolic diseases,particularly type 2 diabetes mellitus, in patients for whom metformintherapy is inappropriate due to intolerability or contraindicationagainst metformin.

The present invention further provides the use of a DPP-4 inhibitor asdefined herein for the manufacture of a pharmaceutical composition fortreating and/or preventing metabolic diseases, particularly type 2diabetes mellitus, in patients for whom metformin therapy isinappropriate due to intolerability or contraindication againstmetformin.

The present invention further provides a pharmaceutical composition foruse in the treatment and/or prevention of metabolic diseases,particularly type 2 diabetes mellitus, in patients for whom metformintherapy is inappropriate due to intolerability or contraindicationagainst metformin, said pharmaceutical composition comprising a DPP-4inhibitor as defined herein and optionally one or more pharmaceuticallyacceptable carriers and/or diluents.

The present invention further provides a fixed or non-fixed combinationincluding a kit-of-parts for use in the treatment and/or prevention ofmetabolic diseases, particularly type 2 diabetes mellitus, in patientsfor whom metformin therapy is inappropriate due to intolerability orcontraindication against metformin, said combination comprising a DPP-4inhibitor as defined herein and optionally one or more other activesubstances, e.g. any of those mentioned herein.

The present invention further provides the use of a DPP-4 inhibitor asdefined herein in combination with one or more other active substances,such as e.g. any of those mentioned herein, for the manufacture of apharmaceutical composition for treatment and/or prevention of metabolicdiseases, particularly type 2 diabetes mellitus, in patients for whommetformin therapy is inappropriate due to intolerability orcontraindication against metformin.

The present invention further provides a pharmaceutical composition foruse in the treatment and/or prevention of metabolic diseases,particularly type 2 diabetes mellitus, in patients for whom metformintherapy is inappropriate due to intolerability or contraindicationagainst metformin, said pharmaceutical composition comprising a DPP-4inhibitor as defined herein and optionally one or more other activesubstances, such as e.g. any of those mentioned herein, such as e.g. forseparate, sequential, simultaneous, concurrent or chronologicallystaggered use of the active ingredients.

The present invention further provides a method of treating and/orpreventing metabolic diseases, particularly type 2 diabetes mellitus, inpatients for whom metformin therapy is inappropriate due tointolerability or contraindication against metformin, said methodcomprising administering to a subject in need thereof (particularly ahuman patient) an effective amount of a DPP-4 inhibitor as definedherein, optionally alone or in combination, such as e.g. separately,sequentially, simultaneously, concurrently or chronologically staggered,with an effective amount of one, two or more other active substances,such as e.g. any of those mentioned herein.

Further, the DPP-4 inhibitors as defined herein may be useful in one ormore of the following methods

-   -   for preventing, slowing progression of, delaying, or treating a        metabolic disorder;    -   for improving glycemic control and/or for reducing of fasting        plasma glucose, of postprandial plasma glucose and/or of        glycosylated hemoglobin HbA1c;    -   for preventing, slowing progression of, delaying or treating of        a condition or disorder selected from the group consisting of        complications of diabetes mellitus;    -   for reducing the weight or preventing an increase of the weight        or facilitating a reduction of the weight;    -   for preventing or treating the degeneration of pancreatic beta        cells and/or for improving and/or restoring the functionality of        pancreatic beta cells and/or stimulating and/or restoring the        functionality of pancreatic insulin secretion; and/or    -   for maintaining and/or improving the insulin sensitivity and/or        for treating or preventing hyperinsulinemia and/or insulin        resistance;

in diabetes patients for whom metformin therapy is inappropriate due tointolerability or contraindication against metformin.

Examples of such metabolic diseases or disorders amenable by the therapyof this invention in patients ineligible for metformin therapy mayinclude, without being restricted to, Type 1 diabetes, Type 2 diabetes,inadequate glucose tolerance, insulin resistance, hyperglycemia,hyperlipidemia, hypercholesterolemia, dyslipidemia, metabolic syndromeX, obesity, hypertension, chronic systemic inflammation, retinopathy,neuropathy, nephropathy, atherosclerosis, endothelial dysfunction andosteoporosis.

The present invention further provides the use of a DPP-4 inhibitor asdefined herein for the manufacture of a medicament for one or more ofthe following purposes:

-   -   preventing, slowing the progression of, delaying or treating a        metabolic disorder or disease, such as e.g. type 1 diabetes        mellitus, type 2 diabetes mellitus, impaired glucose tolerance        (IGT), impaired fasting blood glucose (IFG), hyperglycemia,        postprandial hyperglycemia, overweight, obesity, dyslipidemia,        hyperlipidemia, hypercholesterolemia, hypertension,        atherosclerosis, endothelial dysfunction, osteoporosis, chronic        systemic inflammation, non-alcoholic fatty liver disease        (NAFLD), retinopathy, neuropathy, nephropathy and/or metabolic        syndrome;    -   improving glycemic control and/or for reducing of fasting plasma        glucose, of postprandial plasma glucose and/or of glycosylated        hemoglobin HbA1c;    -   preventing, slowing, delaying or reversing progression from        impaired glucose tolerance (IGT), impaired fasting blood glucose        (IFG), insulin resistance and/or from metabolic syndrome to type        2 diabetes mellitus;    -   preventing, reducing the risk of, slowing the progression of,        delaying or treating of complications of diabetes mellitus such        as micro- and macrovascular diseases, such as nephropathy,        micro- or macroalbuminuria, proteinuria, retinopathy, cataracts,        neuropathy, learning or memory impairment, neurodegenerative or        cognitive disorders, cardio- or cerebrovascular diseases, tissue        ischaemia, diabetic foot or ulcus, atherosclerosis,        hypertension, endothelial dysfunction, myocardial infarction,        acute coronary syndrome, unstable angina pectoris, stable angina        pectoris, peripheral arterial occlusive disease, cardiomyopathy,        heart failure, heart rhythm disorders, vascular restenosis,        and/or stroke;    -   reducing body weight or preventing an increase in body weight or        facilitating a reduction in body weight;    -   preventing, slowing, delaying or treating the degeneration of        pancreatic beta cells and/or the decline of the functionality of        pancreatic beta cells and/or for improving and/or restoring the        functionality of pancreatic beta cells and/or stimulating and/or        restoring the functionality of pancreatic insulin secretion;    -   preventing, slowing, delaying or treating non alcoholic fatty        liver disease (NAFLD) including hepatic steatosis, non-alcoholic        steatohepatitis (NASH) and/or liver fibrosis;    -   preventing, slowing the progression of, delaying or treating        type 2 diabetes with primary or secondary failure to        conventional (oral) antihyperglycemic mono- or combination        therapy;    -   achieving a reduction in the dose of conventional        antihyperglycemic medication required for adequate therapeutic        effect;    -   reducing the risk for adverse effects associated with        conventional antihyperglycemic medication; and/or    -   maintaining and/or improving the insulin sensitivity and/or for        treating or preventing hyperinsulinemia and/or insulin        resistance;

particularly in a patient for whom metformin therapy is inappropriatedue to intolerability or contraindication against metformin and/or whohas renal disease, renal dysfunction, or

insufficiency or impairment of renal function (including patient withchronic renal insufficiency),

optionally in combination with one or more other active substances, suchas e.g. any of those mentioned herein.

Further on, according to a further embodiment of the present invention,it is provided a DPP-4 inhibitor as defined herein for treating and/orpreventing (including reducing the risk of developing or progressing)metabolic disorders or diseases, especially diabetes (particularly type2 diabetes), in patients having renal disease, renal dysfunction, orinsufficiency or impairment of renal function (including patients havingchronic renal insufficiency), optionally in combination with one or moreother active substances, such as e.g. selected from those mentionedherein.

In an embodiment of this invention, patients as described herein who areamenable to the treatment with a DPP-4 inhibitor as defined herein,optionally in (add-on or initial) combination with one or twoconventional antihyperglycemic agents selected from sulphonylureas,thiazolidinediones, glinides, alpha-glucosidase blockers, GLP-1 or GLP-1analogues, and insulin or insulin analogues, may include, without beinglimited to, drug naïve as well as pre-treated diabetes patients, such ase.g. patients with inadequate glycemic control despite conventionalantidiabetic therapy (e.g. primary or secondary drug failure), such ase.g. patients with inadequate glycemic control despite medication with(e.g., if applicable, despite therapy with a maximal tolerated oral doseof) one, two or three conventional antihyperglycemic agents selectedfrom metformin, sulphonylureas, thiazolidinediones, glinides,alpha-glucosidase blockers, GLP-1 or GLP-1 analogues, and insulin orinsulin analogues (e.g. despite mono-therapy with a sulphonylurea,pioglitazone or (basal) insulin, or despite dual combination therapywith a sulphonylurea/pioglitazone, sulphonylurea/(basal) insulin orpioglitazone/(basal) insulin combination).

In a further embodiment of the present invention, it is provided a DPP-4inhibitor as defined herein, optionally in combination with one or moreconventional antihyperglycemic agents selected from sulphonylureas,thiazolidinediones (e.g. pioglitazone), glinides, alpha-glucosidaseblockers, GLP-1 and GLP-1 analogues, and insulin and insulin analogues,for use in (first line) therapy of type 2 diabetes patients for whommetformin therapy is not appropriate (due to intolerance orcontraindication against metformin).

In a further embodiment of the present invention, it is provided a DPP-4inhibitor as defined herein, optionally in combination with one or moreconventional antihyperglycemic agents selected from sulphonylureas,thiazolidinediones (e.g. pioglitazone), glinides, alpha-glucosidaseblockers, GLP-1 and GLP-1 analogues, and insulin and insulin analogues,for use in (second line or third line) therapy of type 2 diabetespatients for whom metformin therapy is not appropriate (due tointolerance or contraindication against metformin) and who areinadequately controlled on said conventional antihyperglycemic agent(s).

In a further embodiment of the present invention, it is provided a DPP-4inhibitor as defined herein in combination with pioglitazone for use intype 2 diabetes patients for whom metformin therapy is not appropriate(due to intolerance or contraindication against metformin) according tothis invention (particularly those who are overweight).

Other aspects of the present invention become apparent to the skilledperson from the foregoing and following remarks.

A DPP-4 inhibitor within the meaning of the present invention includes,without being limited to, any of those DPP-4 inhibitors mentionedhereinabove and hereinbelow, preferably orally active DPP-4 inhibitors.

A special embodiment of this invention refers to a DPP-4 inhibitor foruse in the treatment of type 2 diabetes mellitus in patients withinsufficient glycemic control, for whom metformin therapy isinappropriate due to intolerability or contraindication againstmetformin.

Another special embodiment of this invention refers to a DPP-4 inhibitorfor use in the treatment and/or prevention of metabolic diseases(particularly type 2 diabetes mellitus) in patients for whom metformintherapy is inappropriate due to intolerability or contraindicationagainst metformin (particularly in patients with renal disease, renaldysfunction or renal impairment), characterized in that said DPP-4inhibitor is administered to said patients either in reduced dose levelsor, advantageously, in the same dose levels as to patients with normalrenal function, thus e.g. said DPP-4 inhibitor does not require downwarddosing adjustment for impaired renal function.

A special embodiment of this invention refers to a DPP-4 inhibitor foruse in the treatment of type 2 diabetes mellitus in patients ineligiblefor metformin therapy due to intolerability or contraindication againstmetformin, such as e.g. any of those intolerabilities orcontraindications defined hereinbefore or hereinafter.

Within the meaning of this invention, a special subgroup of the patientsconcerned by the therapies according to this invention refers topatients having chronic renal insufficiency or impairment (particularlyof moderate, severe or terminal stage).

Patients with renal disease, renal dysfunction or renal impairmentrequire a careful assessment for the appropriate choice of theirmedication and dosing regimen, particularly based on the nature andproperties of the individual drug (e.g. its pharmacokinetics,pharmacodynamics, metabolism, elimination pathway) and on patients'grade of renal impairment.

A DPP-4 inhibitor which may be suggested for the purpose of the presentinvention (especially for patients with impaired renal function) may besuch an oral DPP-4 inhibitor, which and whose active metabolites havepreferably a relatively wide (e.g. about >100 fold) therapeutic windowand/or, especially, that are primarily eliminated via hepatic metabolismor biliary excretion.

In more detail, a DPP-4 inhibitor particularly suitable for the purposeof the present invention (especially for patients with impaired renalfunction) may be such an orally administered DPP-4 inhibitor, which hasa relatively wide (e.g. >100 fold) therapeutic window and/or whichfulfils one or more of the following pharmacokinetic properties(preferably at its therapeutic oral dose levels):

-   -   The DPP-4 inhibitor is substantially or mainly excreted via the        liver (e.g. >80% or even >90% of the administered oral dose),        and/or for which renal excretion represents no substantial or        only a minor elimination pathway (e.g. <10%, preferably <7%, of        the administered oral dose measured, for example, by following        elimination of a radiolabelled carbon (¹⁴C) substance oral        dose);    -   The DPP-4 inhibitor is excreted mainly unchanged as parent drug        (e.g. with a mean of >70%, or >80%, or, preferably, 90% of        excreted radioactivity in urine and faeces after oral dosing of        radiolabelled carbon (¹⁴C) substance), and/or which is        eliminated to a non-substantial or only to a minor extent via        metabolism (e.g. <30%, or <20%, or, preferably, 10%);    -   The (main) metabolite(s) of the DPP-4 inhibitor is/are        pharmacologically inactive. Such as e.g. the main metabolite        does not bind to or does not inhibit the activity of the target        enzyme DPP-4 and, optionally, it is rapidly eliminated compared        to the parent compound (e.g. with a terminal half-life of ≤20 h,        or, preferably, ≤about 16 h, such as e.g. 15.9 h).

In one embodiment, the (main) metabolite (which may be pharmacologicallyinactive) of a DPP-4 inhibitor having a 3-amino-piperidin-1-ylsubstituent is such a derivative where the amino group of the3-amino-piperidin-1-yl moiety is replaced by a hydroxyl group to formthe 3-hydroxy-piperidin-1-yl moiety.

Further properties of the DPP-4 inhibitor, which may be attractive forthe purpose of the present invention, may be one or more of thefollowing: Rapid attainment of steady state (e.g. reaching steady stateplasma levels (>90% of the steady state plasma concentration) betweensecond and fifth day of treatment with therapeutic oral dose levels),little accumulation (e.g. with a mean accumulation ratio R_(A,AUC)≤1.4with therapeutic oral dose levels), and/or preserving a long-lastingeffect on DPP-4 inhibition, preferably when used once-daily (e.g. withalmost complete (>90%) DPP-4 inhibition at therapeutic oral doselevels, >80% inhibition over a 24 h interval after once-daily intake oftherapeutic oral drug dose), significant decrease in 2 h postprandialblood glucose excursions by 80% (already on first day of therapy) attherapeutic dose levels, and cumulative amount of unchanged parentcompound excreted in urine on first day being below 1% of theadministered dose and increasing to not more than about 3-6% in steadystate.

Thus, this invention refers also to a DPP-4 inhibitor for use in thetreatment and/or prevention of metabolic diseases (in particular type 2diabetes mellitus in patients for whom metformin therapy isinappropriate due to intolerability or contraindication againstmetformin, in more particular in patients with renal disease, renaldysfunction or renal impairment), characterized in that said DPP-4inhibitor is excreted to a non-substantial or only to a minor extent(e.g. <10%, preferably <7% of administered oral dose) via the kidney(measured, for example, by following elimination of a radiolabelledcarbon (¹⁴C) substance oral dose).

Further, this invention refers to a DPP-4 inhibitor for use in thetreatment and/or prevention of metabolic diseases (in particular type 2diabetes mellitus in patients for whom metformin therapy isinappropriate due to intolerability or contraindication againstmetformin, in more particular in patients with renal disease, renaldysfunction or renal impairment), characterized in that said DPP-4inhibitor is excreted substantially or mainly via the liver (measured,for example, by following elimination of a radiolabelled carbon (¹⁴C)substance oral dose).

Further, this invention refers to a DPP-4 inhibitor for use in thetreatment and/or prevention of metabolic diseases (in particular type 2diabetes mellitus in patients for whom metformin therapy isinappropriate due to intolerability or contraindication againstmetformin, in more particular in patients with renal disease, renaldysfunction or renal impairment), characterized in that

said DPP-4 inhibitor is excreted mainly unchanged as parent drug (e.g.with a mean of >70%, or >80%, or, preferably, 90% of excretedradioactivity in urine and faeces after oral dosing of radiolabelledcarbon (¹⁴C) substance),

said DPP-4 inhibitor is eliminated to a non-substantial or only to aminor extent via metabolism, and/or

the main metabolite of said DPP-4 inhibitor is pharmacologicallyinactive or has a relatively wide therapeutic window.

In a first embodiment (embodiment A), a DPP-4 inhibitor in the contextof the present invention is any DPP-4 inhibitor of

formula (I)

or formula (II)

or formula (III)

or formula (IV)

wherein R1 denotes ([1,5]naphthyridin-2-yl)methyl,(quinazolin-2-yl)methyl, (quinoxalin-6-yl)methyl,(4-methyl-quinazolin-2-yl)methyl, 2-cyano-benzyl,(3-cyano-quinolin-2-yl)methyl, (3-cyano-pyridin-2-yl)methyl,(4-methyl-pyrimidin-2-yl)methyl, or (4,6-dimethyl-pyrimidin-2-yl)methyland R2 denotes 3-(R)-amino-piperidin-1-yl,(2-amino-2-methyl-propyl)-methylamino or(2-(S)-amino-propyl)-methylamino,

or its pharmaceutically acceptable salt.

In a second embodiment (embodiment B), a DPP-4 inhibitor in the contextof the present invention is a DPP-4 inhibitor selected from the groupconsisting of

sitagliptin, vildagliptin, saxagliptin, alogliptin,

-   (2S)-1-{[2-(5-Methyl-2-phenyl-oxazol-4-yl)-ethylamino]-acetyl}-pyrrolidine-2-carbonitrile,-   (2S)-1-{[1,1,-Dimethyl-3-(4-pyridin-3-yl-imidazol-1-yl)-propylamino]-acetyl}-pyrrolidine-2-carbonitrile,-   (S)-1-((2S,3S,11bS)-2-Amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-4-fluoromethyl-pyrrolidin-2-one,-   (3,3-Difluoropyrrolidin-1-yl)-((2S,4S)-4-(4-(pyrimidin-2-yl)piperazin-1-yl)pyrrolidin-2-yl)methanone,-   (1((3S,4S)-4-amino-1-(4-(3,3-difluoropyrrolidin-1-yl)-1,3,5-triazin-2-yl)pyrrolidin-3-yl)-5,5-difluoropiperidin-2-one,-   (2S,4S)-1-{2-[(3S,1R)-3-(1H-1,2,4-Triazol-1-ylmethyl)cyclopentylamino]-acetyl}-4-fluoropyrrolidine-2-carbonitrile,-   (R)-2-[6-(3-Amino-piperidin-1-yl)-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl]-4-fluoro-benzonitrile,-   5-{(S)-2-[2-((S)-2-Cyano-pyrrolidin-1-yl)-2-oxo-ethylamino]-propyl}-5-(1H-tetrazol-5-yl)-10,11-dihydro-5H-dibenzo[a,d]cycloheptene-2,8-dicarboxylic    acid bis-dimethylamide,-   3-{(2S,4S)-4-[4-(3-Methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl]pyrrolidin-2-ylcarbonyl}thiazolidine,-   [(2R)-1-{[(3R)-pyrrolidin-3-ylamino]acetyl}pyrrolidin-2-yl]boronic    acid,-   (2S,4S)-1-[2-[(4-ethoxycarbonylbicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile,-   2-({6-[(3R)-3-amino-3-methylpiperidin-1-yl]-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydro-5H-pyrrolo[3,2-d]pyrimidin-5-yl}methyl)-4-fluorobenzonitrile,    and-   6-[(3R)-3-amino-piperidin-1-yl]-5-(2-chloro-5-fluoro-benzyl)-1,3-dimethyl-1,5-dihydro-pyrrolo[3,2-d]pyrimidine-2,4-dione,-   or its pharmaceutically acceptable salt.

Regarding the first embodiment (embodiment A), preferred DPP-4inhibitors are any or all of the following compounds and theirpharmaceutically acceptable salts:

-   1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine    (compare WO 2004/018468, example 2(142)):

-   1-[([1,5]naphthyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine    (compare WO 2004/018468, example 2(252)):

-   1-[(Quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine    (compare WO 2004/018468, example 2(80)):

-   2-((R)-3-Amino-piperidin-1-yl)-3-(but-2-yinyl)-5-(4-methyl-quinazolin-2-ylmethyl)-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one    (compare WO 2004/050658, example 136):

-   1-[(4-Methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyin-1-yl)-8-[(2-amino-2-methyl-propyl)-methylamino]-xanthine    (compare WO 2006/029769, example 2(1)):

-   1-[(3-Cyano-quinolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine    (compare WO 2005/085246, example 1(30)):

-   1-(2-Cyano-benzyl)-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine    (compare WO 2005/085246, example 1(39)):

-   1-[(4-Methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(S)-(2-amino-propyl)-methylamino]-xanthine    (compare WO 2006/029769, example 2(4)):

-   1-[(3-Cyano-pyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine    (compare WO 2005/085246, example 1(52)):

-   1-[(4-Methyl-pyrimidin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine    (compare WO 2005/085246, example 1(81)):

-   1-[(4,6-Dimethyl-pyrimidin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine    (compare WO 2005/085246, example 1(82)):

-   1-[(Quinoxalin-6-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine    (compare WO 2005/085246, example 1(83)):

These DPP-4 inhibitors are distinguished from structurally comparableDPP-4 inhibitors, as they combine exceptional potency and a long-lastingeffect with favourable pharmacological properties, receptor selectivityand a favourable side-effect profile or bring about unexpectedtherapeutic advantages or improvements when combined with otherpharmaceutical active substances. Their preparation is disclosed in thepublications mentioned.

A more preferred DPP-4 inhibitor among the abovementioned DPP-4inhibitors of embodiment A of this invention is1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine,particularly the free base thereof (which is also known as BI 1356).

Unless otherwise noted, according to this invention it is to beunderstood that the definitions of the active compounds (including theDPP-4 inhibitors) mentioned hereinabove and hereinbelow also comprisetheir pharmaceutically acceptable salts as well as hydrates, solvatesand polymorphic forms thereof. With respect to salts, hydrates andpolymorphic forms thereof, particular reference is made to those whichare referred to herein.

With respect to embodiment A, the methods of synthesis for the DPP-4inhibitors according to embodiment A of this invention are known to theskilled person. Advantageously, the DPP-4 inhibitors according toembodiment A of this invention can be prepared using synthetic methodsas described in the literature. Thus, for example, purine derivatives offormula (I) can be obtained as described in WO 2002/068420, WO2004/018468, WO 2005/085246, WO 2006/029769 or WO 2006/048427, thedisclosures of which are incorporated herein. Purine derivatives offormula (II) can be obtained as described, for example, in WO2004/050658 or WO 2005/110999, the disclosures of which are incorporatedherein. Purine derivatives of formula (III) and (IV) can be obtained asdescribed, for example, in WO 2006/068163, WO 2007/071738 or WO2008/017670, the disclosures of which are incorporated herein. Thepreparation of those DPP-4 inhibitors, which are specifically mentionedhereinabove, is disclosed in the publications mentioned in connectiontherewith. Polymorphous crystal modifications and formulations ofparticular DPP-4 inhibitors are disclosed in WO 2007/128721 and WO2007/128724, respectively, the disclosures of which are incorporatedherein in their entireties. Formulations of particular DPP-4 inhibitorswith metformin or other combination partners are described inPCT/EP2009053978, the disclosure of which is incorporated herein in itsentirety. Typical dosage strengths of the dual combination of BI1356/metformin are 2.5/500 mg, 2.5/850 mg and 2.5/1000 mg.

With respect to embodiment B, the methods of synthesis for the DPP-4inhibitors of embodiment B are described in the scientific literatureand/or in published patent documents, particularly in those citedherein.

For pharmaceutical application in warm-blooded vertebrates, particularlyhumans, the compounds of this invention are usually used in dosages from0.001 to 100 mg/kg body weight, preferably at 0.1-15 mg/kg, in each case1 to 4 times a day. For this purpose, the compounds, optionally combinedwith other active substances, may be incorporated together with one ormore inert conventional carriers and/or diluents, e.g. with corn starch,lactose, glucose, microcrystalline cellulose, magnesium stearate,polyvinylpyrrolidone, citric acid, tartaric acid, water, water/ethanol,water/glycerol, water/sorbitol, water/polyethylene glycol, propyleneglycol, cetylstearyl alcohol, carboxymethylcellulose or fatty substancessuch as hard fat or suitable mixtures thereof into conventional galenicpreparations such as plain or coated tablets, capsules, powders,suspensions or suppositories.

The pharmaceutical compositions according to this invention comprisingthe DPP-4 inhibitors as defined herein are thus prepared by the skilledperson using pharmaceutically acceptable formulation excipients asdescribed in the art. Examples of such excipients include, without beingrestricted to diluents, binders, carriers, fillers, lubricants, flowpromoters, crystallisation retardants, disintegrants, solubilizers,colorants, pH regulators, surfactants and emulsifiers.

Examples of suitable diluents for compounds according to embodiment Ainclude cellulose powder, calcium hydrogen phosphate, erythritol, lowsubstituted hydroxypropyl cellulose, mannitol, pregelatinized starch orxylitol. Among those diluents mannitol, low substituted hydroxypropylcellulose and pregelatinized starch are to be emphasized.

Examples of suitable lubricants for compounds according to embodiment Ainclude talc, polyethyleneglycol, calcium behenate, calcium stearate,hydrogenated castor oil or magnesium stearate. Among those lubricantsmagnesium stearate is to be emphasized.

Examples of suitable binders for compounds according to embodiment Ainclude copovidone (copolymerisates of vinylpyrrolidon with othervinylderivates), hydroxypropyl methylcellulose (HPMC),hydroxypropylcellulose (HPC), polyvinylpyrrolidon (povidone),pregelatinized starch, or low-substituted hydroxypropylcellulose(L-HPC). Among those binders copovidone and pregelatinized starch are tobe emphasized.

Examples of suitable disintegrants for compounds according to embodimentA include corn starch or crospovidone. Among those disintegrants cornstarch is to be emphasized.

Suitable methods of preparing pharmaceutical formulations of the DPP-4inhibitors according to embodiment A of the invention are

-   -   direct tabletting of the active substance in powder mixtures        with suitable tabletting excipients;    -   granulation with suitable excipients and subsequent mixing with        suitable excipients and subsequent tabletting as well as film        coating; or    -   packing of powder mixtures or granules into capsules.

Suitable granulation methods are

-   -   wet granulation in the intensive mixer followed by fluidised bed        drying;    -   one-pot granulation;    -   fluidised bed granulation; or    -   dry granulation (e.g. by roller compaction) with suitable        excipients and subsequent tabletting or packing into capsules.

An exemplary composition of a DPP-4 inhibitor according to embodiment Aof the invention comprises the first diluent mannitol, pregelatinizedstarch as a second diluent with additional binder properties, the bindercopovidone, the disintegrant corn starch, and magnesium stearate aslubricant; wherein copovidone and/or corn starch may be optional.

For details on dosage forms, formulations and administration of DPP-4inhibitors of this invention, reference is made to scientific literatureand/or published patent documents, particularly to those cited herein.

With respect to the first embodiment (embodiment A), the dosagetypically required of the DPP-4 inhibitors mentioned herein inembodiment A when administered intravenously is 0.1 mg to 10 mg,preferably 0.25 mg to 5 mg, and when administered orally is 0.5 mg to100 mg, preferably 2.5 mg to 50 mg or 0.5 mg to 10 mg, more preferably2.5 mg to 10 mg or 1 mg to 5 mg, in each case 1 to 4 times a day. Thus,e.g. the dosage of1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthinewhen administered orally is 0.5 mg to 10 mg per patient per day,preferably 2.5 mg to 10 mg or 1 mg to 5 mg per patient per day.

A dosage form prepared with a pharmaceutical composition comprising aDPP-4 inhibitor mentioned herein in embodiment A contain the activeingredient in a dosage range of 0.1-100 mg. Thus, e.g. particular dosagestrengths of1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthineare 0.5 mg, 1 mg, 2.5 mg, 5 mg and 10 mg.

With respect to the second embodiment (embodiment B), the doses of DPP-4inhibitors mentioned herein in embodiment B to be administered tomammals, for example human beings, of, for example, approximately 70 kgbody weight, may be generally from about 0.5 mg to about 350 mg, forexample from about 10 mg to about 250 mg, preferably 20-200 mg, morepreferably 20-100 mg, of the active moiety per person per day, or fromabout 0.5 mg to about 20 mg, preferably 2.5-10 mg, per person per day,divided preferably into 1 to 4 single doses which may, for example, beof the same size. Single dosage strengths comprise, for example, 10, 25,40, 50, 75, 100, 150 and 200 mg of the DPP-4 inhibitor active moiety.

A dosage strength of the DPP-4 inhibitor sitagliptin is usually between25 and 200 mg of the active moiety. A recommended dose of sitagliptin is100 mg calculated for the active moiety (free base anhydrate) oncedaily. Unit dosage strengths of sitagliptin free base anhydrate (activemoiety) are 25, 50, 75, 100, 150 and 200 mg. Particular unit dosagestrengths of sitagliptin (e.g. per tablet) are 25, 50 and 100 mg. Anequivalent amount of sitagliptin phosphate monohydrate to thesitagliptin free base anhydrate is used in the pharmaceuticalcompositions, namely, 32.13, 64.25, 96.38, 128.5, 192.75, and 257 mg,respectively. Adjusted dosages of 25 and 50 mg sitagliptin are used forpatients with renal failure. Typical dosage strengths of the dualcombination of sitagliptin/metformin are 50/500 mg and 50/1000 mg.

A dosage range of the DPP-4 inhibitor vildagliptin is usually between 10and 150 mg daily, in particular between 25 and 150 mg, 25 and 100 mg or25 and 50 mg or 50 and 100 mg daily. Particular examples of daily oraldosage are 25, 30, 35, 45, 50, 55, 60, 80, 100 or 150 mg. In a moreparticular aspect, the daily administration of vildagliptin may bebetween 25 and 150 mg or between 50 and 100 mg. In another moreparticular aspect, the daily administration of vildagliptin may be 50 or100 mg. The application of the active ingredient may occur up to threetimes a day, preferably one or two times a day. Particular dosagestrengths are 50 mg or 100 mg vildagliptin. Typical dosage strengths ofthe dual combination of vildagliptin/metformin are 50/850 mg and 50/1000mg.

Alogliptin may be administered to a patient at a daily dose of between 5mg/day and 250 mg/day, optionally between 10 mg and 200 mg, optionallybetween 10 mg and 150 mg, and optionally between 10 mg and 100 mg ofalogliptin (in each instance based on the molecular weight of the freebase form of alogliptin). Thus, specific dosage amounts that may be usedinclude, but are not limited to 10 mg, 12.5 mg, 20 mg, 25 mg, 50 mg, 75mg and 100 mg of alogliptin per day. Alogliptin may be administered inits free base form or as a pharmaceutically acceptable salt.

Saxagliptin may be administered to a patient at a daily dose of between2.5 mg/day and 100 mg/day, optionally between 2.5 mg and 50 mg. Specificdosage amounts that may be used include, but are not limited to 2.5 mg,5 mg, 10 mg, 15 mg, 20 mg, 30 mg, 40 mg, 50 mg and 100 mg of saxagliptinper day. Typical dosage strengths of the dual combination ofsaxagliptin/metformin are 2.5/500 mg and 2.5/1000 mg.

A special embodiment of the DPP-4 inhibitors of this invention refers tothose orally administered DPP-4 inhibitors which are therapeuticallyefficacious at low dose levels, e.g. at dose levels <100 mg or <70 mgper patient per day, preferably <50 mg, more preferably <30 mg or <20mg, even more preferably from 1 mg to 10 mg per patient per day (ifrequired, divided into 1 to 4 single doses, particularly 1 or 2 singledoses, which may be of the same size), particularly from 1 mg to 5 mg(more particularly 5 mg), preferentially, administered orallyonce-daily, more preferentially, at any time of day, administered withor without food.

A particularly preferred DPP-4 inhibitor to be emphasized within themeaning of this invention is1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine(also known as BI 1356). BI 1356 exhibits high potency, 24 h duration ofaction, and a wide therapeutic window. In patients with type 2 diabetesreceiving multiple oral doses of 1, 2.5, 5 or 10 mg of BI 1356 oncedaily for 12 days, BI 1356 shows favourable pharmacodynamic andpharmacokinetic profile (see e.g. Table 1 below) with rapid attainmentof steady state (e.g. reaching steady state plasma levels (>90% of thepre-dose plasma concentration on Day 13) between second and fifth day oftreatment in all dose groups), little accumulation (e.g. with a meanaccumulation ratio R_(A,AUC)≤1.4 with doses above 1 mg) and preserving along-lasting effect on DPP-4 inhibition (e.g. with almost complete(>90%) DPP-4 inhibition at the 5 mg and 10 mg dose levels, i.e. 92.3 and97.3% inhibition at steady state, respectively, and >80% inhibition overa 24 h interval after drug intake), as well as significant decrease in 2h postprandial blood glucose excursions by ≥80% (already on Day 1) indoses ≥2.5 mg, and with the cumulative amount of unchanged parentcompound excreted in urine on Day 1 being below 1% of the administereddose and increasing to not more than about 3-6% on Day 12 (renalclearance CL_(R,ss) is from about 14 to about 70 mL/min for theadministered oral doses, e.g. for the 5 mg dose renal clearance is about70 ml/min). In people with type 2 diabetes BI 1356 shows a placebo-likesafety and tolerability. With low doses of about ≥5 mg, BI 1356 acts asa true once-daily oral drug with a full 24 h duration of DPP-4inhibition. At therapeutic oral dose levels, BI 1356 is mainly excretedvia the liver and only to a minor extent (about <7% of the administeredoral dose) via the kidney. BI 1356 is primarily excreted unchanged viathe bile. The fraction of BI 1356 eliminated via the kidneys increasesonly very slightly over time and with increasing dose, so that therewill likely be no need to modify the dose of BI 1356 based on thepatients' renal function. The non-renal elimination of BI 1356 incombination with its low accumulation potential and broad safety marginmay be of significant benefit in a patient population that has a highprevalence of renal insufficiency and diabetic nephropathy.

TABLE 1 Geometric mean (gMean) and geometric coefficient of variation(gCV) of pharmacokinetic parameters of BI 1356 at steady state (Day 12)1 mg 2.5 mg 5 mg 10 mg Parameter gMean (gCV) gMean (gCV) gMean (gCV)gMean (gCV) AUC₀₋₂₄ 40.2 (39.7) 85.3 (22.7)  118 (16.0)  161 (15.7)[nmol · h/L] AUC_(T,ss) 81.7 (28.3)  117 (16.3)  158 (10.1)  190 (17.4)[nmol · h/L] C_(max) [nmol/L] 3.13 (43.2) 5.25 (24.5) 8.32 (42.4) 9.69(29.8) C_(max,ss) 4.53 (29.0) 6.58 (23.0) 11.1 (21.7) 13.6 (29.6)[nmol/L] t_(max)* [h] 1.50 [1.00-3.00] 2.00 [1.00-3.00] 1.75 [0.92-6.02]2.00 [1.50-6.00] t_(max,ss)* [h] 1.48 [1.00-3.00] 1.42 [1.00-3.00] 1.53[1.00-3.00] 1.34 [0.50-3.00] T_(1/2,ss) [h]  121 (21.3)  113 (10.2)  131(17.4)  130 (11.7) Accumulation 23.9 (44.0) 12.5 (18.2) 11.4 (37.4) 8.59(81.2) t_(1/2,) [h] R_(A,Cmax) 1.44 (25.6) 1.25 (10.6) 1.33 (30.0) 1.40(47.7) R_(A,AUC) 2.03 (30.7) 1.37 (8.2)  1.33 (15.0) 1.18 (23.4) fe₀₋₂₄[%] NC 0.139 (51.2)  0.453 (125)   0.919 (115)   fe_(T,ss) [%] 3.34(38.3) 3.06 (45.1) 6.27 (42.2) 3.22 (34.2) CL_(R,ss) 14.0 (24.2) 23.1(39.3)   70 (35.0) 59.5 (22.5) [mL/min] *median and range [min-max] NCnot calculated as most values below lower limit of quantification

As different metabolic functional disorders often occur simultaneously,it is quite often indicated to combine a number of different activeprinciples with one another. Thus, depending on the functional disordersdiagnosed, improved treatment outcomes may be obtained if a DPP-4inhibitor is combined with active substances customary for therespective disorders, such as e.g. one or more active substancesselected from among the other antidiabetic substances, especially activesubstances that lower the blood sugar level or the lipid level in theblood, raise the HDL level in the blood, lower blood pressure or areindicated in the treatment of atherosclerosis or obesity.

The DPP-4 inhibitors mentioned above—besides their use inmono-therapy—may also be used in conjunction with other activesubstances, by means of which improved treatment results can beobtained. Such a combined treatment may be given as a free combinationof the substances or in the form of a fixed combination, for example ina tablet or capsule.

Pharmaceutical formulations of the combination partner(s) needed forthis may either be obtained commercially as pharmaceutical compositionsor may be formulated by the skilled man using conventional methods. Theactive substances which may be obtained commercially as pharmaceuticalcompositions are described in numerous places in the prior art, forexample in the list of drugs that appears annually, the “Rote Liste®” ofthe federal association of the pharmaceutical industry, or in theannually updated compilation of manufacturers' information onprescription drugs known as the “Physicians' Desk Reference”.

Examples of antidiabetic combination partners are sulphonylureas such asglibenclamide, tolbutamide, glimepiride, glipizide, gliquidon,glibornuride and gliclazide; nateglinide; repaglinide;thiazolidinediones such as rosiglitazone and pioglitazone; PPAR gammamodulators such as metaglidases; PPAR-gamma agonists such as GI 262570;PPAR-gamma antagonists; PPAR-gamma/alpha modulators such astesaglitazar, muraglitazar, aleglitazar, indeglitazar, AVE0897 andKRP297; PPAR-gamma/alpha/delta modulators; AMPK-activators such asAICAR; acetyl-CoA carboxylase (ACC1 and ACC2) inhibitors;diacylglycerol-acetyltransferase (DGAT) inhibitors; pancreatic beta cellGCRP agonists such as SMT3-receptor-agonists and GPR119;11β-HSD-inhibitors; FGF19 agonists or analogues; alpha-glucosidaseblockers such as acarbose, voglibose and miglitol; alpha2-antagonists;insulin and insulin analogues such as human insulin, insulin lispro,insulin glusilin, r-DNA-insulinaspart, NPH insulin, insulin detemir,insulin zinc suspension and insulin glargin; Gastric inhibitory Peptide(GIP); pramlintide, davalintide; amylin and amylin analogues or GLP-1and GLP-1 analogues such as Exendin-4, e.g. exenatide, exenatide LAR,liraglutide, taspoglutide, AVE-0010, LY-2428757, LY-2189265, semaglutideor albiglutide; SGLT2-inhibitors such as KGT-1251; inhibitors of proteintyrosine-phosphatase (e.g. trodusquemine); inhibitors ofglucose-6-phosphatase; fructose-1,6-bisphosphatase modulators; glycogenphosphorylase modulators; glucagon receptor antagonists;phosphoenolpyruvatecarboxykinase (PEPCK) inhibitors; pyruvatedehydrogenasekinase (PDK) inhibitors; inhibitors of tyrosine-kinases (50mg to 600 mg) such as PDGF-receptor-kinase (cf. EP-A-564409, WO98/35958, U.S. Pat. No. 5,093,330, WO 2004/005281, and WO 2006/041976);glucokinase/regulatory protein modulators incl. glucokinase activators;glycogen synthase kinase inhibitors; inhibitors of theSH2-domain-containing inositol 5-phosphatase type 2 (SHIP2); IKKinhibitors such as high-dose salicylate; JNK1 inhibitors; protein kinaseC-theta inhibitors; beta 3 agonists such as ritobegron, YM 178,solabegron, talibegron, N-5984, GRC-1087, rafabegron, FMP825;aldosereductase inhibitors such as AS 3201, zenarestat, fidarestat,epalrestat, ranirestat, NZ-314, CP-744809, and CT-112; SGLT-1 or SGLT-2inhibitors, such as e.g. dapagliflozin, sergliflozin, atigliflozin,larnagliflozin or canagliflozin (or compound of formula (I-S) or (I-K)from WO 2009/035969); KV 1.3 channel inhibitors; GPR40 modulators; SCD-1inhibitors; CCR-2 antagonists; dopamine receptor agonists (bromocriptinemesylate [Cycloset]); and other DPP IV inhibitors.

A dosage of the partner drug pioglitazone is usually of about 1-10 mg,15 mg, 30 mg, or 45 mg once a day.

Rosiglitazone is usually given in doses from 4 to 8 mg once (or dividedtwice) a day (typical dosage strengths are 2, 4 and 8 mg).

Glibenclamide (glyburide) is usually given in doses from 2.5-5 to 20 mgonce (or divided twice) a day (typical dosage strengths are 1.25, 2.5and 5 mg), or micronized glibenclamide in doses from 0.75-3 to 12 mgonce (or divided twice) a day (typical dosage strengths are 1.5, 3, 4.5and 6 mg).

Glipizide is usually given in doses from 2.5 to 10-20 mg once (up to 40mg divided twice) a day (typical dosage strengths are 5 and 10 mg), orextended-release glipizide in doses from 5 to 10 mg (up to 20 mg) once aday (typical dosage strengths are 2.5, 5 and 10 mg).

Glimepiride is usually given in doses from 1-2 to 4 mg (up to 8 mg) oncea day (typical dosage strengths are 1, 2 and 4 mg).

A dual combination of glibenclamide/metformin is usually given in dosesfrom 1.25/250 once daily to 10/1000 mg twice daily (typical dosagestrengths are 1.25/250, 2.5/500 and 5/500 mg).

A dual combination of glipizide/metformin is usually given in doses from2.5/250 to 10/1000 mg twice daily (typical dosage strengths are 2.5/250,2.5/500 and 5/500 mg).

A dual combination of glimepiride/metformin is usually given in dosesfrom 1/250 to 4/1000 mg twice daily.

A dual combination of rosiglitazone/glimepiride is usually given indoses from 4/1 once or twice daily to 4/2 mg twice daily (typical dosagestrengths are 4/1, 4/2, 4/4, 8/2 and 8/4 mg).

A dual combination of pioglitazone/glimepiride is usually given in dosesfrom 30/2 to 30/4 mg once daily (typical dosage strengths are 30/4 and45/4 mg).

A dual combination of rosiglitazone/metformin is usually given in dosesfrom 1/500 to 4/1000 mg twice daily (typical dosage strengths are 1/500,2/500, 4/500, 2/1000 and 4/1000 mg).

A dual combination of pioglitazone/metformin is usually given in dosesfrom 15/500 once or twice daily to 15/850 mg thrice daily (typicaldosage strengths are 15/500 and 15/850 mg).

The non-sulphonylurea insulin secretagogue nateglinide is usually givenin doses from 60 to 120 mg with meals (up to 360 mg/day, typical dosagestrengths are 60 and 120 mg); repaglinide is usually given in doses from0.5 to 4 mg with meals (up to 16 mg/day, typical dosage strengths are0.5, 1 and 2 mg). A dual combination of repaglinide/metformin isavailable in dosage strengths of 1/500 and 2/850 mg.

Acarbose is usually given in doses from 25 to 100 mg with meals (up to300 mg/day, typical dosage strengths are 25, 50 and 100 mg). Miglitol isusually given in doses from 25 to 100 mg with meals (up to 300 mg/day,typical dosage strengths are 25, 50 and 100 mg).

Conventional antidiabetics and antihyperglycemics typically used inmono- or dual or triple (add-on or initial) combination therapy mayinclude, without being limited to, metformin, sulphonylureas,thiazolidinediones, glinides, alpha-glucosidase blockers, GLP-1 andGLP-1 analogues, as well as insulin and insulin analogues, such as e.g.those agents indicated herein by way of example, including combinationsthereof.

For the purpose of this invention, particular antidiabetic partner drugsfor the combined use with the DPP-4 inhibitors according to thisinvention may include, without being limited to, particularly forpatients with moderate renal impairment, glibenclamide (reduced dose),glimepiride (reduced dose), gliquidon (reduced dose), glipizide,repaglinide, acarbose, miglitol, rosiglitazone and pioglitazone; as wellas, particularly for patients with severe renal impairment, repaglinide(reduced dose), pioglitazone and insulin and insulin analogues.

Examples of combination partners that lower the lipid level in the bloodare HMG-CoA-reductase inhibitors such as simvastatin, atorvastatin,lovastatin, fluvastatin, pravastatin, pitavastatin and rosuvastatin;fibrates such as bezafibrate, fenofibrate, clofibrate, gemfibrozil,etofibrate and etofyllinclofibrate; nicotinic acid and the derivativesthereof such as acipimox; PPAR-alpha agonists; PPAR-delta agonists;inhibitors of acyl-coenzyme A:cholesterolacyltransferase (ACAT; EC2.3.1.26) such as avasimibe; cholesterol resorption inhibitors such asezetimib; substances that bind to bile acid, such as cholestyramine,colestipol and colesevelam; inhibitors of bile acid transport; HDLmodulating active substances such as D4F, reverse D4F, LXR modulatingactive substances and FXR modulating active substances; CETP inhibitorssuch as torcetrapib, JTT-705 (dalcetrapib) or compound 12 from WO2007/005572 (anacetrapib); LDL receptor modulators; and ApoB100antisense RNA.

A dosage of the partner drug atorvastatin is usually from 1 mg to 40 mgor 10 mg to 80 mg once a day

Typical lipid-lowering partner drugs may include, without being limitedto, statins (e.g. atorvastatin, simvastatin, pravastatin, fluvastatin,lovastatin or rosuvastatin), ezetimibe, fibrates (e.g. fenofibrate orgemfibrozil), CETP inhibitors, bile acid sequestrants (e.g.cholestyramine or colesevelam), and nicotinic acid or nicotinic acidderivatives (which also increase blood HDL level), as well ascombinations thereof (e.g. a statin/ezetimibe or statin/fibratecombination). Particularly for patients with moderate or severe renalimpairment, typical lipid lowering drugs may include, without beinglimited to, atorvastatin, fluvastatin, gemfibrozil, ezetemibe, andfenofibrate, as well as combinations thereof (e.g. aatorvastatin/ezetimibe; fluvastatin/ezetimibe; statin/fenobif rate orfluvastatin/gemfibrozil, each optionally plus ezetimibe; combination).Particularly for patients with ESRD, typical lipid lowering drugs mayinclude, without being limited to, atorvastatin, fluvastatin,gemfibrozil, and ezetemibe, as well as combinations thereof (e.g. aatorvastatin/ezetimibe or fluvastatin/ezetimibe combination).

Examples of combination partners that lower blood pressure arebeta-blockers such as atenolol, bisoprolol, celiprolol, metoprolol andcarvedilol; diuretics such as hydrochlorothiazide, chlortalidon,xipamide, furosemide, piretanide, torasemide, spironolactone,eplerenone, amiloride and triamterene; calcium channel blockers such asamlodipine, nifedipine, nitrendipine, nisoldipine, nicardipine,felodipine, lacidipine, lercanipidine, manidipine, isradipine,nilvadipine, verapamil, gallopamil and diltiazem; ACE inhibitors such asramipril, lisinopril, cilazapril, quinapril, captopril, enalapril,benazepril, perindopril, fosinopril and trandolapril; as well asangiotensin II receptor blockers (ARBs) such as telmisartan,candesartan, valsartan, losartan, irbesartan, olmesartan and eprosartan.

A dosage of the partner drug telmisartan is usually from 20 mg to 320 mgor 40 mg to 160 mg per day.

Typical blood pressure-lowering partner drugs may include, without beinglimited to, ACE inhibitors (ACEi) (e.g. ramipril, lisinopril, quinapril,captopril, enalapril, benazepril, perindopril, trandolapril, fosinoprilor moexipril), ARBs (e.g. telmisartan, candesartan, valsartan, losartan,irbesartan, olmesartan or eprosartan), calcium channel blockers (CCBs)(e.g. non-dihydropyridine CCBs such as diltiazem or verapamil, ordihydropyridine CCBs such as amlodipine, felodipine, nisoldipine ornifedipine), thiazide-type diuretics (e.g. hydrochlorothiazide orchlorthialidone), alpha-blockers, and beta blockers (e.g. atenolol,carvedilol or metoprolol), as well as combinations thereof (e.g. aACEi/ARB, ACEi/beta blocker, ARB/beta blocker, ACEi/diuretic,ARB/diuretic, ACEi/CCB or ARB/CCB combination).

Examples of combination partners which increase the HDL level in theblood are Cholesteryl Ester Transfer Protein (CETP) inhibitors;inhibitors of endothelial lipase; regulators of ABC1; LXRalphaantagonists; LXRbeta agonists; PPAR-delta agonists; LXRalpha/betaregulators, and substances that increase the expression and/or plasmaconcentration of apolipoprotein A-I.

Examples of combination partners for the treatment of obesity aresibutramine; tetrahydrolipstatin (orlistat), cetilistat; alizyme;dexfenfluramine; axokine; cannabinoid receptor 1 antagonists such as theCB1 antagonist rimonobant; MCH-1 receptor antagonists; MC4 receptoragonists; NPY5 as well as NPY2 antagonists; beta3-AR agonists such asSB-418790 and AD-9677; 5HT2c receptor agonists such as APD 356(lorcaserin); myostatin inhibitors; Acrp30 and adiponectin; steroyl CoAdesaturase (SCD1) inhibitors; fatty acid synthase (FAS) inhibitors; CCKreceptor agonists; Ghrelin receptor modulators; Pyy 3-36; orexinreceptor antagonists; and tesofensine; as well as the dual combinationsbupropion/naltrexone, bupropion/zonisamide, topiramate/phentermine andpramlintide/metreleptin.

Examples of combination partners for the treatment of atherosclerosisare phospholipase A2 inhibitors; inhibitors of tyrosine-kinases (50 mgto 600 mg) such as PDGF-receptor-kinase (cf. EP-A-564409, WO 98/35958,U.S. Pat. No. 5,093,330, WO 2004/005281, and WO 2006/041976); oxLDLantibodies and oxLDL vaccines; apoA-1 Milano; ASA; and VCAM-1inhibitors.

For the use of the herein-mentioned drugs in patients with renaldisease, renal dysfunction or renal insufficiency, it may be required insome cases—depending on the individual drug (e.g. its pharmacokinetics,pharmacodynamics, metabolism, elimination pathway) and on patient'sgrade of renal impairment—to adjust or reduce its dose for patient'simpaired renal function.

The present invention is not to be limited in scope by the specificembodiments described herein. Various modifications of the invention inaddition to those described herein may become apparent to those skilledin the art from the present disclosure. Such modifications are intendedto fall within the scope of the appended claims.

All patent applications cited herein are hereby incorporated byreference in their entireties.

Further embodiments, features and advantages of the present inventionmay become apparent from the following examples. The following examplesserve to illustrate, by way of example, the principles of the inventionwithout restricting it.

EXAMPLES

The usability of a DPP-4 inhibitor according to this invention for thepurpose of the present invention can be tested using clinical trials:

For example, in a randomised, double-blind, parallel group trial, thesafety and efficacy of a DPP-4 inhibitor according to the invention(e.g. 5 mg of BI 1356 administered orally once daily) is compared withplacebo over a treatment period of 18 weeks, followed by a 34 weekdouble-blind extension period (placebo switched to glimepiride) inpatients with type 2 diabetes and insufficient glycemic control (e.g.HbA1c 7% to 10%) who are ineligible for metformin therapy due tointolerability or contraindications against metformin.

Patients ineligible for metformin therapy defined as:

contraindications against metformin therapy according to label, forexample:

-   -   renal disease or renal dysfunction (e.g., as specified by        product information of locally approved metformin),    -   dehydration by clinical judgement of the investigator,    -   unstable or acute congestive heart failure,    -   acute or chronic metabolic acidosis (present condition in        patient history),    -   hereditary galactose intolerance;

or documented intolerable side effects attributed to metformin, forexample:

-   -   nausea,    -   vomiting,    -   diarrhoea,    -   intestinal gas,    -   severe abdominal discomfort.

In this study the efficacy a DPP-4 inhibitor according to this inventionin this patient population is investigated over the shorter termtreatment period of 18 weeks and safety/tolerability over the longerterm treatment period for a maximum of 52 weeks in comparison to asulfonylurea drug (glimepiride).

The success of the treatment is tested by determining the HbA1c value,by comparison with the initial value and/or with the value of theplacebo group. A significant change in the HbA1c value compared with theinitial value and/or the placebo value demonstrates the efficacy of theDPP-4 inhibitor for the treatment. The success of the treatment can bealso tested by determining the fasting plasma glucose values, bycomparison with the initial values and/or with the values of the placebogroup. A significant drop in the fasting glucose levels demonstrates theefficacy of the treatment. Also, the occurrence of a treat to targetresponse (i.e. an HbA1c under treatment <7% or <6.5%) demonstrates theefficacy of the treatment.

The safety and tolerability of the treatment is investigated byassessing patient's condition and relevant changes from baseline, e.g.incidence and intensity of adverse events (such as e.g. renal adverseevents, hypoglycaemic episodes or the like) or weight gain underglimepiride therapy compared to DPP-4 inhibitor treatment.

For other example, in a randomised, double-blind, parallel group trial,the safety, efficacy and tolerability of a DPP-4 inhibitor according tothe invention (e.g. 5 mg of BI 1356) is compared with placebo over atreatment period of 52 weeks in type 2 diabetic male and female patientswith severe chronic renal impairment (GFR <30 ml/min, who are not onchronic dialysis), including patients on insulin and/or sulfonylureabackground medication.

The safety and tolerability of the treatment is investigated byassessing patient's condition. The efficacy can be investigated bychange from baseline in HbA1c after 12 weeks treatment, by change infasting plasma glucose parameters, or by change in insulin and/orsulfonylurea dosage at 52 weeks compared to baseline and over time.

Metabolism and elimination properties of a DPP-4 inhibitor for thepurpose of this invention:

The excretion pathways, mass balance and metabolism of a DPP-4 inhibitoraccording to this invention in a human subject can be investigated usinga radiolabelled (e.g. [14C]-labelled) DPP-4 inhibitor for oraladministration, such as e.g. as follows for a compound determined to besuitable for the purpose of the present invention:

Following oral administration of 10 mg [14C]BI 1356/subject (e.g.healthy male volunteer), the total radioactivity is primarily eliminatedvia the feces with a mean of 83.8% of the administered dose excretedwithin 16 days. Renal excretion accounts for 6.6% of the administereddose after 9 days post dose. Recovery of total radioactivity ranges from86.1%-95.1% (mean: 90.4%) of the administered dose.

After oral administration of [14C]BI 1356, the parent compound is themost abundant radioactive species in all matrices investigated. Inplasma, the parent compound [14C]BI 1356 accounts for a mean of 74% ofsample radioactivity (sample pool: 1.5+3+6 h) after oral administration.The inactive main metabolite is identified in plasma with 16.9% ofsample radioactivity in pooled samples. The parent compound [14C]BI 1356is excreted unchanged in urine and feces with a mean of 90% of excretedradioactivity after oral dosing. Metabolites, including the mainmetabolite, account individually for <10% in the excreta.

What is claimed is:
 1. A method of treating and/or preventing ametabolic disorder in a patient for whom metformin therapy isinappropriate due to contraindication against metformin comprisingorally administering3-{(2S,4S)-4-[4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl]pyrrolidin-2-ylcarbonyl}thiazolidine,or a pharmaceutically acceptable salt thereof, to the patient, whereinthe metabolic disorder is type 2 diabetes mellitus and thecontraindication is renal impairment, and wherein3-{(2S,4S)-4-[4-(3-Methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl]pyrrolidin-2-ylcarbonyl}thiazolidine,or a pharmaceutically acceptable salt thereof, is administered to thepatient in the same dose as for a patient with normal renal function. 2.The method according to claim 1 wherein the patient is ineligible formetformin therapy due to contraindication against metformin.
 3. Themethod according to claim 1 wherein the patient is in need of reduceddose metformin therapy due to contraindication against metformin.
 4. Themethod according to claim 1, wherein3-{(2S,4S)-4-[4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl]pyrrolidin-2-ylcarbonyl}thiazolidineand its major active metabolite(s) have a relatively wide therapeuticwindow and/or are primarily eliminated via hepatic metabolism or biliaryexcretion.
 5. The method according to claim 1, wherein3-{(2S,4S)-4-[4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl]pyrrolidin-2-ylcarbonyl}thiazolidineis excreted mainly via the liver.
 6. The method according to claim 1,for which excretion via the kidney represents a minor eliminationpathway of3-{(2S,4S)-4-[4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl]pyrrolidin-2-ylcarbonyl}thiazolidine.7. The method according to claim 1, wherein3-{(2S,4S)-4-[4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl]pyrrolidin-2-ylcarbonyl}thiazolidineis excreted mainly unchanged.
 8. The method according to claim 1, forwhich elimination of3-{(2S,4S)-4-[4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl]pyrrolidin-2-ylcarbonyl}thiazolidinevia metabolism represents a minor elimination pathway.
 9. The methodaccording to claim 1, wherein3-{(2S,4S)-4-[4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl]pyrrolidin-2-ylcarbonyl}thiazolidinehas placebo-like safety/tolerability and/or is eliminated primarily asthe parent drug via the liver.
 10. The method according to claim 1,wherein the main metabolite of3-{(2S,4S)-4-[4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl]pyrrolidin-2-ylcarbonyl}thiazolidineis pharmacologically inactive or has a relatively wide therapeuticwindow.
 11. The method according to claim 1 wherein the contraindicationis mild, moderate or severe renal impairment or end-stage renal disease.12. The method according to claim 1, wherein3-{(2S,4S)-4-[4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl]pyrrolidin-2-ylcarbonyl}thiazolidine,or a pharmaceutically acceptable salt thereof, is administered incombination with one or more further active substances selected fromantidiabetics, active substances that lower the blood sugar level,active substances that lower the lipid level in the blood, activesubstances that raise the HDL level in the blood, active substances thatlower the blood pressure, active substances that are indicated in thetreatment of atherosclerosis, and active substances that are indicatedin the treatment of obesity.
 13. The method according to claim 1,wherein3-{(2S,4S)-4-[4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl]pyrrolidin-2-ylcarbonyl}thiazolidine,or a pharmaceutically acceptable salt thereof, is administered incombination with one or more further active substances selected fromsulphonylureas, thiazolidinediones, glinides, alpha-glucosidaseblockers, GLP-1 and GLP-1 analogues, and insulin and insulin analogues.14. The method according to claim 1, wherein3-{(2S,4S)-4-[4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl]pyrrolidin-2-ylcarbonyl}thiazolidine,or a pharmaceutically acceptable salt thereof, is administered incombination with one or more further active substances selected fromrepaglinide, pioglitazone, and insulin and insulin analogues.
 15. Themethod according to claim 1, wherein3-{(2S,4S)-4-[4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl]pyrrolidin-2-ylcarbonyl}thiazolidine,or a pharmaceutically acceptable salt thereof, is administered incombination with pioglitazone.